2,3-Polymethylene-4-oxo-4H-pyrido[1,2-a]pyrimidines

ABSTRACT

Pharmaceutical intermediates, morphine potentiators and other compounds have the formula ##STR1## wherein R is hydrogen, halogen, C 1-4  alkyl, hydroxy, nitro, amino, carboxy or a carboxylic acid derivate radical, R 1  is hydrogen or a C 1-4  alkyl, R 2  is hydrogen or C 1-4  alkyl, R 3  is hydrogen, R 4  is hydrogen or C 1-4  alkyl, R 5  is hydrogen R 6  is hydrogen or R 3  and R 4  and/or R 5   and R 6  form a chemical bond, X is oxygen or imino, m is 1, 2, 3 or 4, n is 0, 1, 2 or 3, and if n is 1, then the dotted lines can stand for bonds, with the proviso that if m=1 and n=1 and if in the 2,3-, 6,7-, 8,9- and 1,10-positions double bonds are present, and R 1  and R 2  are hydrogen, then R is other than 9-hydroxy or 9-methyl; if m=2 and n=1 and R 2  is hydrogen, then at least one of R and R 1  is other than hydrogen; and if m=2 and n=2 and R 2  is hydrogen and the molecule is a 2,3,4,6,7,8,9,10-octahydro derivative, then at least one of R and R 1  is other than hydrogen or an acid-addition or quaternary salt thereof.

The present invention relates to tricyclic nitrogen bridge-headcompounds, acid-addition salts and quaternary salts thereof and to aprocess for the preparation of the above compounds.

The preparation of only a few similar compounds has been reported in theprior art. Thus, for example, 2-aminopyridine and2-ethoxycarbonyl-cyclohexanone were reacted in polyphosphoric acid ethylester at 165° C. and after chromatographing on an alumina column2,3-tetramethylene-4-oxo-4H-pyrido(1,2-a)pyrimidine was prepared with ayield of 50% (J. Chem. Soc. C 1971, 2163).2,3-Tetramethylene-4-oxo-6,7,8,9-tetrahydro-4-H-pyrido(1,2-a)-pyrimidinewas prepared with a 78% yield from an inner salt of11-oxo-1,2,3,4,5,7,8,9,10,11-decahydro-pyrido-(1,2-b)cinnoline-6-iumhydroxide in a Photoisomerization reaction lasting 5 days. The samecompound was prepared with only a 14% yield by heating2-imino-piperidine hydrochloride and 2-ethoxycarbonyl-cyclohexanoneunder nitrogen atmosphere in acetic acid in a reaction lasting 20 hours(J. Org. Chem. 40, 2201, 1975). Recently, 2-amino-pyridine, and somederivatives theeof substituted in the 3-position have been reacted with2-ethoxycarbonyl-cyclopentanone optionally in the presence of an inertsolvent. As a catalyst concentrated sulfuric acid, methane sulfonicacid, p-toluene sulfonic acid or an ion-exchanger resin in acid phasemay be used in the reaction. This method results in 50-68% of2,3-trimethylene-4-oxo-4H-pyrido-(1,2-a)pyrimidine derivatives, patentedas tranquillizers and as antianxiolythic compounds (U.S. Pat. No.3,965,100).

2-Amino-cyclohexane-carboxylic acid and2-methoxy-4,5,6,7-tetrahydro-3H-azepine were reported to react with eachother in acetone for 2 hours to produce2,3-tetramethylene-4-oxo-2,3,4,6,7,8,9,10-octahydro-pyrido(1,2-a)-azepine,melting at 100° C. (U.S. Pat. No. 2,992,221 and GFR Pat. No. 1,088,968).

The invention is based partly on the recognition that the ring closuremay be carried out with a good yield in the presence of phosphoric acidunder acidic conditions or in the presence of aromatic tertiary aminesunder basic conditions with the elimination of the chromatographic stepand partly that the new compounds exhibit an analgesic andmorphine-potentiating activity and may be used as a therapeuticallyactive analgesic pharmaceutical compositions.

The invention relates to new compounds of the formula I ##STR2## andacid-addition salts and quaternary salts thereof--wherein R is hydrogenor halogen, C₁₋₄ alkyl, hydroxy, nitro, amino, carboxy, or a carboxylicacid derivative radical,

R¹ is hydrogen or C₁₋₄ alkyl,

R² is hydrogen or C₁₋₄ alkyl,

R³ is hydrogen,

R⁴ is hydrogen or C₁₋₄ alkyl,

R⁵ is hydrogen,

R⁶ is hydrogen or R³ and R⁴ and/or R⁵ and R⁶ form a chemical bond,

X is oxygen or imino,

m is 1, 2, 3 or 4,

n is 0, 1, 2 or 3 and if n is 1, then the dotted lines can be bonds,with the proviso that if m=1 and n=1 and if in the 2,3-, 6,7-8,9- and1,10-positions double bonds are present and and R¹ and R² are hydrogen,then R is other than 9-hydroxy or 9-methyl and if m=2 and n=1 and R² ishydrogen, then at least one of R and R¹ is different from hydrogen andif m=2 and n=2 and R² is hydrogen and the molecule is a2,3,4,6,7,8,9,10-octahydro-derivative then at least one of R and R¹ isother than hydrogen.

The term "C₁₋₄ alkyl" as used hereinafter means straight or branchedC₁₋₄ alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl. The term "halogen" means chlorine, bromine, iodine orfluorine. The term "carhoxylic acid derivative radical" means carboxylicacid esters (such as alkyl, aryl, or aralkyl esters, preferablyalkoxycarbonyl, phenyloxycarbonyl, or benzyloxycarbonyl), acid amides(such as carbamoyl or N-alkyl or N,N-dialkylcarbamoyl), acid azides,acid hydrazides or nitriles.

Preferred are those compounds of the formula I wherein

R is hydrogen, methyl, ethyl, chlorine, bromine, nitro, amino, carboxy,methoxy carbonyl, ethoxycarbonyl or carbamoyl,

R¹ is hydrogen or methyl,

R² is hydrogen, methyl, ethyl or tertiary butyl,

R³, R⁴, R⁵ and R⁶ are hydrogen or R³ and R⁴ and/or R⁵ and R⁶ togetherform a chemical bond,

X is oxygen, and n=0, 1 or 2 and

m is 1 to 4, and the acid-addition and quaternary salts thereof.

Particularly preferred are the following compounds of the formula I

7-methyl-2,3-trimethylene-4-oxo-4H-pyrido(1,2-a)pyrimidine andacid-addition salts and quaternary salts thereof,

8-methyl-2,3-trimethylene-4-oxo-4H-pyrido(1,2-a)pyrimidine,acid-addition salts and quaternary salts thereof,

6,8-dimethyl-2,3-trimethylene-4-oxo-4H-pyrido(1,2-a)-pyrimidine andacid-addition salts and quaternary salts thereof,

6-methyl-2,3-tetramethylene-4-oxo-4H-pyrido(1,2-a)pyrimidine, salts andquaternary salts thereof,

2,3-pentamethylene-4-oxo-4-H-pyrido(1,2-a)pyrimidine, acid-additionsalts and quaternary acid-addition salts thereof,

2,3-hexamethylene-4-oxo-4H-pyrido(1,2-a)pyrimidine, acid-addition saltsand quaternary salts thereof.

The invention further relates to a process for the preparation oftricyclic nitrogen bridge-head compounds of the formula I ##STR3## saltsand quaternary salts thereof--wherein R is hydrogen or halogen, C₁₋₄alkyl, hydroxy, nitro, amino, carboxy or a carboxylic acid derivativeradical,

R¹ is hydrogen or C₁₋₄ alkyl,

R² is hydrogen or C₁₋₄ alkyl,

R³ is hydrogen, R⁴ is hydrogen or C₁₋₄ alkyl, R⁵ is hydrogen, R⁶ ishydrogen or R³ and R⁴ and/or R⁵ and R⁶ can form together a chemical bond

X is oxygen or imino,

m is 1, 2, 3 or 4, n is 0, 1, 2, or 3 and if n is 1, the dotted linesstand for a double bond, comprising

(a) reacting a 2-amino-pyridine derivative of the formula II ##STR4## oran acid-addition salt thereof with a cyclic oxo compound of the formulaIII wherein R⁷ is alkoxycarbonyl containing C₁₋₄ alkyl, a carboxylicacid radical, carboxamido or nitrile and if2,3-trimethylene-9-methyl-4-oxo-4H-pyrido(1,2-a)pyrimidine,

2,3-trimethylene-9-hydroxy-4-oxo-4H-pyrido(1,2-a)pyrimidine,

2,3-trimethylene-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-(1,2-a)pyrimidine,or

2,3-tetramethylene-4-oxo-2,3,4,6,7,8,9,10-octahydropyrido(1,2-a)azepine-

is prepared, the reaction is carried out in the presence of phosphoricacid or an aromatic tertiary amine, or

(b) condensing an amine of the formula IV ##STR5## with a cyclic oxocompound of the formula III, in an inert solvent, optionally in thepresence of phosphoric acid, or

(c) condensing an imino ether of the formula V ##STR6## wherein R⁸ isC₁₋₄ alkyl with an amine of the formula VI ##STR7## in an inert solvent,in the presence of phosphoric acid, and reducing, if desired theobtained compound of the formula I--wherein the dotted lines are anoptional bonds and R³ and R⁴ and/or R⁵ and R⁶ form a chemical bond--inorder to reduce the double bonds in the regions of the dotted linesand/or the double bonds formed between R³ -R⁴ and/or R⁵ -R⁶, andconverting, if desired the obtained compound of the formula I to an acidaddition or quaternary salt and/or reducing the obtained quaternary saltand/or setting free a compound of the formula I from its salt andconverting, if desired, the obtained compound of the formula I toanother compound of the formula I.

According to an embodiment of the step (a) of the invention2-amino-pyridine derivatives of the formula II or an acid-addition saltthereof are reacted with a cyclic oxo compound of the formula IIIwherein

R⁷ is alkoxycarbonyl containing C₁₋₄ alkyl, carboxylic acid, carboxamidoor nitrile -

obtaining nitrogen bridgehead compounds of the formula I wherein

n is 1, the dotted lines are double bonds, and

R³ and R⁴ and/or R⁵ and R⁶ form a chemical bond.

2-amino-pyridine of the formula II or an acid-addition salt thereof iscondensed with a cyclic oxo compound of the formula III, preferably inthe presence of phosphoric acid. The condensation may, however, also becarried out by reacting the acid addition salt of 2-amino-pyridine ofthe formula II with the cyclic oxo compound of the formula III in thepresence of an aromatic tertiary amine. In step (b) a compound of theformula IV is condensed with a cyclic oxo-compound of the generalformula III by heating the mixture in an inert solvent, if desired, inthe presence of an acid condensing agent, preferably phosphoric acid orpolyphosphoric acid. Thus nitrogen bridgehead compounds of the formula Iare obtained wherein R³ and R⁴, R⁵ and R⁶ form a chemical bond. In step(c) of the method, an imino ehter of the formula V wherein R⁸ is C₁₋₄alkyl is condensed with an amine of the formula VI - with heating of themixture in an inert solvent, if desired in the presence of an acidcondensing agent, preferably phosphoric acid or polyphosphoric acid.Thus nitrogen bridgehead compounds of the formula I are obtained whereinR³ and R⁴ form a chemical bond.

The pyrido (1,2-a)pyrimidine compound of the formula I obtained by anyof steps (a), (b) and (c) -wherein at least the dotted lines are partsof double bonds, or R³ and R⁴ and/or R⁵ and R⁶ form a chemical bond - isreduced if desired, by a complex metal hydride or catalyticallyactivated hydrogen.

The obtained nitrogen bridgehead compound of the formula I can beconverted, if desired, to an acid-addition or quaternary salt, or may beset free from the acid-addition salt, or the quaternary salt may bereduced.

When condensing 2-amino-pyridine of the formula II or an acid-additionsalt thereof with a cyclic oxo compound of the formula III as phosphoricacid, preferably polyphosphoric acid can be used. The reaction mixturemay be further processed by diluting the reaction mixture with water andneutralizing it with a 10% by W/V alkaline solution, preferably sodiumhydroxide under cooling. The precipitated crystals can be filtered orcentrifuged to recover the crystals. The condensation can also becarried out by using phosphorus trichloride oxide as solvent and thusthe necessary amount of the polyphosphoric acid may be reduced. Whenfurther processing the reaction mixture it is decomposed with alcoholand the hydrochloride salt precipitates from the cooled reaction mixturein the form of crystals, which may be recovered by filtration. Thereaction mixture may also be decomposed with an aqueous alkalinesolution when carrying out the ring closure in the presence ofphosphorus trichloride oxide. In this case the ring-closed compound isobtained in the form of a base. The ring closure can be carried out at20° to 250° C., preferably at 80° to 160° C.

Condensation of the hydrohaloide of 2-amino-pyridine of the formula IIwith a cyclic oxo compound of the formula III is preferably carried outin the presence of an aromatic tertiary nitrogen-containing base. Asaromatic tertiary nitrogen-containing bases pyridine, picoline,quinoline, luthidine etc. are preferably employed. The reaction ispreferably carried out at the boiling point of the solvent used. Thereaction mixture is evaporated at reduced pressure and crystallized fromalcohol. Thus hydrohalides are obtained.

The base is, if desired, set free from the hydrohaloides by methodsknown per se.

As inert solvents in the method steps (b) and (c) alcohols (preferablymethanol or ethanol), aromatic hydrocarbons (benzene, toluene, xylene),halogenated hydrocarbons (chloroform, dichloromethane, chlorobenzene,carbon-tetrachloride), ketones (acetone, ethyl-methyl-ketone), esters(such as ethyl acetate) may be used. The reaction is preferably carriedout at the boiling point of the inert solvent. The residue afterevaporation is crystallized from a suitable solvent or solvent mixture.The reaction may also be performed in the presence of an acid condensingagent. As acid condensing agents phosphoric acid, preferablypolyphosphoric acid may be employed. The reaction is performed at 20° to250° C., preferably at 80° to 160° C. The reaction mixture is furtherprocessed by diluting with water, followed by neutralization with analkaline solution, preferably with 10% by W/V sodium hydroxide solution.The precipitated crystals may be removed by filtration.

If R is nitro in the tricyclic nitrogen bridgehead compounds of theformula I, then the reaction may be carried out in aqueous medium withmetallic iron under the circumstances of the Bechamp reduction and thusthe nitro group is reduced to an amino group.

Palladium and Raney nickel or platina, platinaoxide may preferably beused as catalysts during the catalytic hydrogenation, which ispreferably carried out at 0° to 50° C., at atmospheric to 10 atm.overpressure in the presence of an inert solvent.

As inert solvents preferably alcohols may be employed. The reducedproduct may be recovered after removing the catalyst by filtration,followed by evaporation of the obtained solution. When performing thereduction with complex metal hydrides, preferably sodiumborohydride,sodiumcyanoborohydride, sodium-bis(2-methoxy-ethoxy) aluminum hydrideor, lithiumaluminum hydride may be used. As a solvent water, alcohol,benzene, ether or, tetrahydrofuran may be employed depending on thecomplex metal hydride used.

The reduction may preferably be carried out at 0° to 50° C. The reducedproduct is recovered by removing the solvent by distillation or if wateris used, by shaking out with a water-immiscible organic solvent(chloroform, benzene, ethyl acetate) and by evaporation of the organicsolvent.

In the quaternizing reaction the usually employed quaternizing agents,such as alkyl halides (ethyl iodide, methyl bromide, methyl chloride),aralkyl halides (benzyl chloride), alkyl sulfates (dimethyl sulfate,diethyl sulfate), benzene sulfonates and alkylated derivatives thereof(benzene sulfonic acid methyl ester, p-toluenesulfonic acid ethylester), alkyl phosphates (trimethyl phosphate, triethyl phosphate),tetraalkyloxonium fluoroborate etc. may be employed. The reaction may beperformed in an excess of the quaternizing agent or an inert solvent ata temperature of 0° to 200° C. As an inert solvent apolar aromatichydrocarbons, such as benzene or toluene, halogenated hydrocarbons(chloroform, chlorobenzene), ethers (dioxan), or aprotic dipolarsolvents, dimethylformamide or nitrides (acetonitrile), nitratedhydrocarbons (nitromethane, nitrobenzene), ketones (acetone,ethyl-methyl-ketone), hexamethyl-phosphortriamide or solvent mixturesare preferred.

In the quaternizing reaction the formed quaternary salt precipitatesfrom the reaction mixture and may be removed, for example by filtration.

From the nitrogen bridgehead comounds of the formula I, acid-additionsalts may be formed with pharmaceutically accepted organic acids orinorganic acids by methods known per se. Thus hydrohalides, such ashydrochlorides, hydrobromides, hydroiodides, salts of sulfuric acid,phosphoric acid, perchloric acid, formic acid, acetic acid, citric acid,maleic acid etc., are preferably prepared.

An obtained compound of the formula I, may be converted, if desired, toanother compound of the formula I by methods known per se. Thus, forexample, a compound of the formula I containing carboxy as R may beconverted to a compound of the formula I, wherein R is hydrogen and thecorresponding esters or amides may be obtained by esterification oramidation. The invention also includes these additional conversions.

Compounds of the formulae II, III, IV, V or VI may be prepared fromcommercially available compounds by methods known per se or thecompounds themselves are commercially available.

The invention also includes the possible stereo isomers of nitrogenbridgehead compounds of the formula I.

The prepared compounds can be useful as active ingredients ofpharmaceutical compositions or as intermediate products in the synthesisof biologically active compounds.

Compounds of the invention have antiinflammatory, analygesic,antipyretic activity, or other favorable activity upon the centralnervous system (such as sedative, hypnotic, tranquillizer activity;other compounds have PG-antagonistic, thrombocyte aggregationinhibiting, anti-asthmatic activity, favorable circulation andanti-arteriosclerotic activity.

Some representatives of the compounds of the invention have significantantibacterial and antimicrobial activity.

Some of the derivatives have particularly significant analgesic andmorphine-potentiating activity. The corresponding test results are to befound in Table 1.

In testing for toxicity the mice were observed for 48 hours afteradministration of the compounds, whereafter the LD₅₀ values weredetermined by the Litchfield-Wilcoxon graphic method. Also the analgesicand morphine-potentiating activities were investigated on mice. The testresults obtained in a "hot plate" test (J. Pharm. Exp. Therp. 80 130(1944) and Kiserl. Orvostudomany 2, 295 (1950) and results obtained inlaparotomic test of Knoll (Animal and Clinical Pharmacologic Techniquesin Drug Evaluation. Vol. 2. 305-321 (1967), Year Book Publ. Chicago) areshown in Table 1.

                  Table 1                                                         ______________________________________                                                                    Dose potentiating                                                             the activity of                                                     Hot plate 5 mg. morphine                                              LD.sub.50                                                                             ED.sub.50 ED.sub.50                                                   mg./kg. mg./kg.   mg./kg.                                           Compound    i.v.   s.c.   i.v. s.c. i.v.                                      ______________________________________                                        7-Methyl-2,3-tri-                                                             methylene-4-oxo-                                                              4H-pyrido(1,2-a)-                                                             pyrimidine hydro-                                                             chloride    120    --     47   --   1.0                                       8-methyl-2,3-tri-                                                             methylene-4-oxo-                                                              4H-pyrido(1,2-a)-                                                             pyrimidine hydro-                                                             chloride    120    --     65   --   4.8                                       6,8-dimethyl-2,3-                                                             trimethylene-4-                                                               oxo-4H-pyrido-                                                                (1,2-a)pyrimidine                                                             hydrochloride                                                                             120    --     42   --   1.0                                       6-methyl-2,3-tetra-                                                           methylene-4-oxo-                                                              4H-pyrido(1,2-a)-                                                             pyrimidine hydro-                                                             chloride    160    --     --   --   7.8                                       2,3-pentamethylene-                                                           4-oxo-4H-pyrido-                                                              (1,2-a)pyrimidine-                                                            hydrochloride                                                                             210    630    --   66   3.7                                       2,3-hexamethylene-                                                            4-oxo-4H-pyrido-                                                              (1,2-a)pyrimidine                                                             hydrochloride                                                                             125    500    --   105  4.5                                       PROBON      220    790    43   75   25.0                                      ______________________________________                                    

As the reference compound the analgesic PROBON.sup.® used and thecorresponding data therefor are also given in the Table. The outstandingmorphine-potentiating activity of the compounds can be seen from thedata of the Table. The compounds similarly potentiate the analgesics ofthe morphine type and other major analgetica, and thus their therapeuticdose may be reduced to a great extent whereby the detrimental sideeffects are also reduced.

The nitrogen bridgehead tricyclic compounds of the formula I can be usedas active ingredients in compositions containing inert, nontoxic solidor liquid diluents or carriers. The compositions may be used in solid(tablets, capsules, dragee etc.) or liquid (such as solution,suspension, emulsion) form.

As carriers, the usual substances such as talcum, calcium carbonate,magnesium stearate, water, polyethylene glycolate etc. may be used. Thecompositions may contain, if desired, usual additives, such asdisintegrating agents, emulsifying agents as well.

Tricyclic nitrogen bridgehead compounds of the formula I may be combinedin the compositions mentioned above with other analgesic compounds suchas morphine derivatives (morphine, azidomorphine, azidocodeine),morphinine derivatives, benzomorphane compounds (phenazocine,pentazocine), phenylpiperidine derivatives (petidine, nisentile). Thelatter derivatives may be used in a smaller dose due to the synergisticactivity upon combination with the compounds of the invention and thusthe unfavorable side effects (tolerance, dependency, breath depression)practically need not be considered.

Further details of the invention are illustrated in the followingExamples.

EXAMPLES 1 TO 20

20 mmoles of 2-ethoxycarbonyl-1-oxo-cycloalkane (see Table 2) and 20mmoles of 2-amino-pyridine are stirred together in 20 g. ofpolyphosphoric acid for 90 minutes at 100° C. The reaction mixture isdiluted with 20 ml. of water and after cooling the pH-value of themixture is adjusted to 7 by adding 10% by W/V of sodium hydroxidesolution. The precipitated crystals are filtered, washed with a smallamount of water and dried. The obtained nitrogen bridgehead compound isrecrystallized from the given solvent. The obtained compounds and theirconstants are summarized in Table 2.

                                      Table 2                                     __________________________________________________________________________    Starting material                                     Analysis                2-ethoxycar-                            Recrystalli-  Calculated              bonyl-1-oxo- 2-amino-         Yield                                                                              Mp.  zation                                                                              Empirical                                                                             Found                   Example                                                                            cycloalkane                                                                           pyridine                                                                            Product    %    °C.                                                                         solvent                                                                             formula C                                                                                H                                                                                N                 __________________________________________________________________________                                                                %                 1    2-ethoxycar-                                                                          2-amino-                                                                            2,3-trimethylene-                                               bonyl-1-oxo-                                                                          pyridine                                                                            4-oxo-4H-pyrido-     diisopropyl-  70.95                                                                            5.41                                                                             15.05                  cyclopentane  (1,2-a)pyrimidine                                                                        66   151-152                                                                            ether C.sub.11 H.sub.10 N.sub.2                                                             70.78                                                                            5.67                                                                             15.26             2    2-ethoxycar-                                                                          2-amino-                                                                            2,3-trimethylene-                  71.98                                                                            6.04                                                                             13.99                  bonyl-1-oxo-                                                                          6-methyl-                                                                           6-methyl-4-oxo-                                                                          84   160-161                                                                            ethanol                                                                             C.sub.12 H.sub.12 N.sub.2                                                             71.75                                                                            6.27                                                                             14.37                  cyclopentane                                                                          pyridine                                                                            4H-pyrido(1,2-a)                                                              pyrimidine                                                 3.sup.x                                                                            2-ethoxycar-                                                                          2-amino-                                                                            2,3-trimethylene-                                               bonyl-1-oxo-                                                                          5-methyl-                                                                           7-methyl-4-oxo-                    71.98                                                                            6.04                                                                             13.99                  cyclopentane                                                                          pyridine                                                                            4H-pyrido(1,2-a)-                                                                        72   145-146                                                                            ethanol                                                                             C.sub.12 H.sub.12 N.sub.2                                                             71.70                                                                            6.25                                                                             13.72                                pyrimidine                                                 4    2-ethoxycar-                                                                          2-amino-                                                                            2,3-trimethylene-                                               bonyl-1-oxo-                                                                          4-methyl-                                                                           8-methyl-4-oxo-      ethyl-        71.98                                                                            6.04                                                                             13.99                  cyclopentane                                                                          pyridine                                                                            4H-pyrido(1,2-a)-                                                                        84   168-169                                                                            acetate                                                                             C.sub.12 H.sub.12 N.sub.2                                                             72.04                                                                            6.03                                                                             13.76                                pyrimidine                                                 5.sup.+                                                                            2-ethoxycar-                                                                          2-amino-                                                                            2,3-trimethylene-                                               bonyl-1-oxo-                                                                          3-methyl-                                                                           9-methyl-4-oxo-                    71.98                                                                            6.04                                                                             13.99                  cyclopentane                                                                          pyridine                                                                            4H-pyrido(1,2-a)                                                                         81   109  ethanol                                                                             C.sub.12 H.sub.12 N.sub.2                                                             71.79                                                                            6.12                                                                             13.78                                pyrimidine                                                 6    2-ethoxycar-                                                                          2-amino-                                                                            2,3-trimethylene-                                               bonyl-1-oxo-                                                                          4,6-di-                                                                             6,8-dimethyl-4-                    72.86                                                                            6.59                                                                             13.08                  cyclopentane                                                                          methyl-                                                                             oxo-4H-pyrido-                                                                           81   163-164                                                                            ethanol                                                                             C.sub.13 H.sub.14 N.sub.2                                                             72.90                                                                            6.59                                                                             12.76                          pyridine                                                                            (1,2-a)pyrimidine                                          6    2-ethoxycar-                                                                          2-amino-                                                                            2,3-trimethylene-                                               bonyl-1-oxo-                                                                          5-pyri-                                                                             7-chloro-4-oxo-                    59.88                                                                            4.11                                                                             12.69                  cyclopentane                                                                          dine  4H-pyrido(1,2-a)-                                                                        82   151-152                                                                            ethanol                                                                             C.sub.11 H.sub.9 N.sub.2                                                      ClO     59.68                                                                            3.98                                                                             13.18                                pyrimidine                                                 8.sup.++                                                                           2-ethoxycar-                                                                          2-amino-                                                                            2,3-trimethylene-                                               bonyl-1-oxo-                                                                          3-hydroxy-                                                                          9-hydroxy-4-oxo-     70% by        65.33                                                                            4.98                                                                             13.86                  cyclopentane                                                                          pyridine                                                                            4H-pyrido(1,2-a)-                                                                        69   159  weight                                                                              C.sub.11 H.sub.10 N.sub.2                                                     O.sub.2 65.22                                                                            5.12                                                                             13.74                                pyrimidine           ethanol                               9    2-ethoxycar-                                                                          2-amino-                                                                            2,3-trimethylene-                  57.14                                                                            3.92                                                                             18.18                  bonyl-1-oxo-                                                                          5-nitro-                                                                            7-nitro-4-oxo-4H-                                                                        45   168-169                                                                            ethanol                                                                             C.sub.11 H.sub.9 N.sub.3                                                      O.sub.3 56.84                                                                            4.13                                                                             17.70                  cyclopentane                                                                          pyridine                                                                            pyrido(1,2-a)-                                                                pyrimidine                                                 10   2-ethoxycar-                                                                          2-amino-                                                                            2,3-(1-methyl-                                                  bonyl-1-oxo-                                                                          6-methyl-                                                                           trimethylene)-6-                   72.86                                                                            6.59                                                                             13.08                  5-methyl-                                                                             pyridine                                                                            methyl-4-oxo-4H-                                                                         76   86-87                                                                              ether C.sub.13 H.sub.14 N.sub.2                                                             72.74                                                                            6.71                                                                             13.12                  cyclopentane  pyrido(1,2-a)-                                                                pyrimidine                                                 11   2-ethoxycar-                                                                          2-amino-                                                                            2,3-(2-tertiary-                                                bonyl-1-oxo-                                                                          6-methyl-                                                                           butyl-trimethylene)-                                            4-tertiary-                                                                           pyridine                                                                            6-methyl-4-oxo-                    74.96                                                                            7.86                                                                             10.93                  butyl-cyclo-  4H-pyrido(1,2-a)-                                                                        57   147  ether C.sub.16 H.sub.20 N.sub.2                                                             74.87                                                                            7.92                                                                             11.12                  pentane       pyrimidine                                                 12.sup.+++                                                                         2-ethoxycar-                                                                          2-amino-                                                                            2,3-tetramethylene-                                             bonyl-1-oxo-                                                                          pyridine                                                                            4-oxo-4H-pyrido-                                                                         86   103-104                                                                            diisopropyl                                                                         Ch.sub.11 H.sub.10 N.sub.2                                                    O       71.98                                                                            6.04                                                                             13.99                  cyclohexane   (1,2-a)pyrimidine    ether         71.87                                                                            6.09                                                                             14.02             13   2-ethoxycar-                                                                          2-amino-                                                                            2,3-tetramethylene-                72.86                                                                            6.59                                                                             13.08                  bonyl-1-oxo-                                                                          6-methyl-                                                                           6-methyl-4-oxo-4H                                               cyclohexane                                                                           pyridine                                                                            pyrido(1,2-a)-                                                                           67   122-123                                                                            ethanol                                                                             C.sub.13 H.sub.14 N.sub.2                                                             72.60                                                                            6.87                                                                             14.02                                pyrimidine                                                 14   2-ethoxycar-                                                                          2-amino-                                                                            2,3-tetramethylene-                                             bonyl-1-oxo-                                                                          3-hydroxy-                                                                          9-hydroxy-4-oxo-     70% by        66.65                                                                            5.59                                                                             12.96                  cyclohexane                                                                           pyridine                                                                            4H-pyrido(1,2-a)-                                                                        71   129  weight                                                                              C.sub.12 H.sub.12 N.sub.2                                                     O.sub.2 66.72                                                                            5.64                                                                             13.00                                pyrimidine           alcohol                               15   2-ethoxycar-                                                                          2-amino-                                                                            2,3-pentamethylene-                                             bonyl-1-oxo-                                                                          pyridine                                                                            4-oxo-4H-pyrido-                                                                         84   136  ethyl-                                                                              C.sub.13 H.sub.14 N.sub.2                                                             72.86                                                                            6.59                                                                             13.08                  cycloheptane  (1,2-a)pyrimidine    acetate       72.63                                                                            6.98                                                                             12.95             16   2-ethoxycar-                                                                          2-amino-                                                                            2,3-pentamethylene-                                             bonyl-1-oxo-                                                                          6-methyl-                                                                           6-methyl-4-oxo-                    73.65                                                                            7.06                                                                             12.27                  cycloheptane                                                                          pyridine                                                                            4H-pyrido(1,2-a)-                                                                        61   97-98                                                                              diisopropyl-                                                                        C.sub.14 H.sub.16 N.sub.2                                                             73.50                                                                            7.20                                                                             12.66                                pyrimidine           ether                                 17   2-ethoxycar-                                                                          2-amino-                                                                            2,3-pentamethylene-  70% by        68.00                                                                            5.84                                                                             11.70                  bonyl-1-oxo-                                                                          3-hydroxy-                                                                          9-hydroxy-4-oxo-                                                cycloheptane                                                                          pyridine                                                                            4H-pyrido(1,2-a)-                                                                        64   137-138                                                                            weight                                                                              C.sub.13 H.sub.14 N.sub.2                                                     O.sub.2 67.92                                                                            6.04                                                                             12.31                                pyrimidine           ethanol                               18   2-ethoxycar-                                                                          2-amino-                                                                            2,3-hexamethylene-                 73.65                                                                            7.06                                                                             12.27                  bonyl-1-oxo-                                                                          pyridine                                                                            4-oxo-4H-pyrido-                                                                         66   114-115                                                                            diisopropyl-                                                                        C.sub.14 H.sub.16 N.sub.2                                                             73.65                                                                            6.94                                                                             12.44                  cyclooctane   (1,2-a)pyrimidine    ether                                 19   2-ethoxycar-                                                                          2-amino-                                                                            2,3-hexamethylene-                                              bonyl-l-oxo-                                                                          bonyl-1-oxo-                                                                        6-methyl-4-oxo-                    74.35                                                                            7.49                                                                             11.56                  cyclooctane                                                                           pyridine                                                                            4H-pyrido(1,2-a)-                                                                        75   102  ethanol                                                                             C.sub.15 H.sub.18 N.sub.2                                                             74.20                                                                            7.32                                                                             11.39                                pyrimidine                                                 20   2-ethoxycar-                                                                          2-amino-                                                                            2,3-hexamethylene-   70% by        68.83                                                                            6.60                                                                             11.47                  bonyl-1-oxo-                                                                          3-hydroxy-                                                                          9-hydroxy-4-oxo-                                                                         62   156-158                                                                            weight                                                                              C.sub.14 H.sub.16 N.sub.2                                                             68.42                                                                            6.54                                                                             11.23                                pyrimidine                                                 __________________________________________________________________________     *The product is recovered by extraction with chloroform                       .sup.+ USP No. 3 965 100; Yield 60%; melting point 100°-102.degree     C.                                                                            .sup.++ USP No. 3 965 100; Yield 55%; melting point                           136°-142° C.                                                    .sup.+++ J. Chem. Soc. C.: 1971, 2153; Yield 50%; melting point               101.5°-103° C.                                                  .sup.+++ J. Chem. Soc. C. 1970, 881; Yield 60%; melting point                 99°-102° C.                                                

EXAMPLES 21 to 35

0.1 mole of 2-ethoxycarbonyl-1-oxo-cycloalkane according to Table 3 and0.1 mole of 2-amino-pyridine are stirred in a mixture of 28 ml. ofphosphorus trichloride oxide and 7.0 g. of polyphosphoric acid for 3hours at 100° C. The reaction mixture is decomposed at 70° to 80° C.with 100 ml. of ethanol. The mixture is cooled and the precipitatedhydrochloride salt is filtered off and washed with ethanol, dried andcrystallized from the given solvent. The prepared compounds andconstants thereof are summarized in Table 3.

                                      Table 3                                     __________________________________________________________________________    Starting material                                     Analysis                2-ethoxycar-                           Recrystalli-   Calculated              bonyl-l-oxo- 2-amino-         Yield                                                                              Mp. zation                                                                              Empirical                                                                              Found                   Example                                                                            cycloalkane                                                                           pyridine                                                                           Product    %    ° C.                                                                        solvent                                                                             formula  C                                                                                H                                                                                N                 __________________________________________________________________________                                                                %                 21   2-ethoxycar-                                                                          2-amino-                                                                           2,3-trimethylene-                                                bonyl-1-oxo-                                                                          pyridine                                                                           4-oxo-4H-pyrido-                                                                         64   166-167                                                                            ethanol-                                                                            C.sub.11 H.sub.11 N.sub.2                                                     ClO      59.33                                                                            4.98                                                                             15.92                  cyclopentane (1,2-a)pyrimidine-   ether          59.00                                                                            5.15                                                                             16.01                               hydrochloride                                               22   2-ethoxycar-                                                                          2-amino-                                                                           2,3-trimethylene-                                                bonyl-1-oxo-                                                                          6-methyl-                                                                          6-methyl-4-oxo-                                                  cyclopentane                                                                          pyridine                                                                           4H-pyrido(1,2-a)     ethanol-                                                                            C.sub.12 H.sub.13 N.sub.2                                                     ClO      60.89                                                                            5.54                                                                             14.98                               pyrimidine-                                                                              67   221-224                                                                            ether          60.45                                                                            5.49                                                                             14.51                               hydrochloride                                               23   2-ethoxycar-                                                                          2-amino-                                                                           2,3-trimethylene-                   60.89                                                                            5.54                                                                             14.98                  bonyl-1-oxo-                                                                          5-methyl-                                                                          7-methyl-4-oxo-                                                  cyclopentane                                                                          pyridine                                                                           4H-pyrido(1,2-a)                                                                         86   206-215                                                                            ethanol                                                                             C.sub.12 H.sub.13 N.sub.2                                                     ClO      60.74                                                                            5.21                                                                             14.64                               pyrimidine-                                                                   hydrochloride                                               24   2-ethoxycar-                                                                          2-amino-                                                                           2,3-trimethylene-                                                bonyl-1-oxo-                                                                          4-methyl-                                                                          8-methyl-4-oxo-      ethanol-       60.89                                                                            5.54                                                                             14.98                  cyclopentane                                                                          pyridine                                                                           4H-pyrido(1,2-a)-                                                                        80   202-210                                                                            ether C.sub.12 H.sub.13 N.sub.2                                                     ClO      60.37                                                                            6.11                                                                             14.94                               pyrimidine-                                                                   hydrochloride                                               25   2-ethoxycar-                                                                          2-amino-                                                                           2,3-trimethylene-                                                bonyl-1-oxo-                                                                          3-methyl-                                                                          9-methyl-4-oxo-4H                                                cyclopentane                                                                          pyridine                                                                           pyrido(1,2-a)-                                                                           77   170-180                                                                            ethanol-                                                                            C.sub.12 H.sub.13 N.sub.2                                                     ClO      60.89                                                                            5.54                                                                             14.98                               pyrimidine-          ether          60.87                                                                            5.84                                                                             14.32                               hydrochloride                                               26   2-ethoxycar-                                                                          2-amino-                                                                           2,3-trimethylene-                                                bonyl-1-oxo-                                                                          4,6-di-                                                                            6,8-dimethyl-4-oxo-  ethanol-       62.27                                                                            6.03                                                                             14.14                  cyclopentane                                                                          methyl-                                                                            4H-pyrido(1,2-a)-                                                                        72   190-203                                                                            ether C.sub.13 H.sub.15 N.sub.2                                                     ClO      62.42                                                                            6.14                                                                             13.92                          pyridine                                                                           pyrimidine-hydro-                                                             chloride                                                    27   2-ethoxycar-                                                                          2-amino-                                                                           2,3-trimethylene-                   51.39                                                                            3.92                                                                             13.79                  bonyl-1-oxo-                                                                          5-chloro-                                                                          7-chloro-4-oxo-                                                  cyclopentane                                                                          pyridine                                                                           4H-pyrido(1,2-a)-                                                                        76   203-206                                                                            ethanol                                                                             C.sub.11 H.sub.10 N.sub.2                                                     Cl.sub.2 O                                                                             51.39                                                                            4.00                                                                             13.51                               pyrimidine-hydro-                                                             chloride                                                    28   2-ethoxycar-                                                                          2-amino-                                                                           2,3-(1-methyl-tri-                                               bonyl-1-oxo-                                                                          6-methyl-                                                                          methylene)-6-                                                    5-methyl-                                                                             pyridine                                                                           methyl-4-oxo-4H-                                                 cyclopentane pyrido(1,2-a)-                                                                           68   178-188                                                                            ethanol-                                                                            C.sub.13 H.sub.15 N.sub.2                                                     ClO      62.27                                                                            6.03                                                                             14.14                               pyrimidine-          ether          61.97                                                                            6.04                                                                             13.61                               hydrochloride                                               29   2-ethoxycar-                                                                          2-amino-                                                                           2,3-(2-tertiary-                                                 bonyl-1-oxo-                                                                          6-methyl-                                                                          butyl-trimethylene)-                                             4-tertiary-                                                                           pyridine                                                                           6-methyl-4-oxo-                                                  butyl-cyclo- 4H-pyrido(1,2-a)-    ethanol-                                                                            C.sub.16 H.sub.21 N.sub.2                                                     ClO      65.63                                                                            7.23                                                                             12.11                  pentane      pyrimidine-hydro-                                                                        45   195-200                                                                            ether          65.88                                                                            7.09                                                                             12.65                               chloride                                                    30   2-ethoxycar-                                                                          2-amino-                                                                           2,3-tetramethylene-                 60.89                                                                            5.54                                                                             14.98                  bonyl-1-oxo-                                                                          pyridine                                                                           4-oxo-4H-pyrido-     ethanol-                                                                            C.sub.12 H.sub.13 N.sub.2                                                     ClO      60.56                                                                            5.56                                                                             14.91                  cyclohexane  (1,2-a)pyrimidine-   ether                                                    hydrochloride                                               31   2-ethoxycar-                                                                          2-amino-                                                                           2,3-tetramethylene-                                              bonyl-1-oxo-                                                                          6-methyl-                                                                          6-methyl-4-oxo-4H-   ethanol-       62.27                                                                            6.03                                                                             14.14                  cyclohexane                                                                           pyridine                                                                           pyrido(1,2-a)-                                                                           62   211-218                                                                            ether C.sub.13 H.sub.15 N.sub.2                                                     ClO      61.82                                                                            6.05                                                                             14.09                               pyrimidine-hydro-                                                             chloride                                                    32   2-ethoxycar-                                                                          2-amino-                                                                           2,3-pentamethylene-                 62.27                                                                            6.04                                                                             14.14                  bonyl-1-oxo-                                                                          pyridine                                                                           4-oxo-4H-pyrido-                                                 cyclohexane  (1,2-a)pyrimidine-                                                                       81   175-181                                                                            ethanol-                                                                            C.sub.13 H.sub.15 N.sub.2                                                     ClO      62.20                                                                            5.77                                                                             14.08                               hydrochloride        ether                                  33   2-ethoxycar-                                                                          2-amino-                                                                           2,3-pentamethylene-                 63.51                                                                            6.47                                                                             13.39                  bonyl-1-oxo-                                                                          6-methyl-                                                                          6-methyl-4-oxo-4H-   ethanol-                                                                            C.sub.14 H.sub.17 N.sub. 2                                                    ClO                                   cycloheptane                                                                          pyridine                                                                           pyrido(1,2-a)-                                                                           58   222-227                                                                            ether          64.10                                                                            7.00                                                                             13.36                               pyrimidine-hydro-                                                             chloride                                                    34   2-ethoxycar-                                                                          2-amino-                                                                           2,3-hexamethylene-                                               bonyl-1-oxo-                                                                          pyridine                                                                           4-oxo-4H-pyrido-                                                 cyclooctane  (1,2-a)pyrimidine-   ethanol        63.51                                                                            6.47                                                                             13.39                               hydrochloride                                                                            62   192-203                                                                            ether C.sub.14 H.sub.17 N.sub.2                                                     ClO      63.20                                                                            6.03                                                                             13.18             35   2-ethoxycar-                                                                          2-amino-                                                                           2,3-hexamethylene-                                               bonyl-1-oxo                                                                           6-methyl-                                                                          6-methyl-4-oxo-4H-   ethanol        64.62                                                                            6.87                                                                             12.72                  cyclooctane                                                                           pyridine                                                                           pyrido(1,2-a)-                                                                           68   200-206                                                                            ether C.sub.15 H.sub.19 N.sub.2                                                     ClO      63.95                                                                            6.99                                                                             12.64                               pyrimidine-hydro-                                                             chloride                                                    __________________________________________________________________________

EXAMPLE 36

15.6 g. of 2-ethoxycarbonyl-1-oxo-cyclopentane and 10.8 g. of2-amino-6-methyl-pyridine are stirred in a water-bath in the mixture of28 ml. of phosphorus trichlorideoxide and 7.0 g. of polyphosphoric acidfor 3 hours. The reaction mixture is cooled and decomposed cautiouslywith 50 ml. of water under external cooling with ice and neutralizedwith 10% by W/V sodium hydroxide solution. The precipitated oil iscrystallized on triturating. The obtained crystals are filtered, washedwith water, dried and crystallized from ethanol. 17 g. (85%) of2,3-trimethylene-6-methyl-4-oxo-4H-pyrido(1,2-a) pyrimidine are obtainedwhich product melts at 160° to 161° C. and by admixing it with theproduct of Example 2, the melting point is not depressed.

EXAMPLE 37

0.02 moles of 2-amino-pyridine-hydrochloride is boiled under reflux for16 hours with 0.03 moles of 2-ethoxycarbonyl-1-oxo-cyclopentane in 50ml. of pyridine. The solvent and the unreacted2-ethoxycarbonyl-1-oxo-cyclopentane are distilled at reduced pressureand the residue is crystallized from a mixture of ethanol and ether.2.15 g. (48%) of 2,3-trimethylene-4-oxo-4H-pyrido(1,2-a)pyrimidinehydrochloride are obtained, melting point: 222°-224° C. and admixed withthe product according to Example 22. The melting point is not depressed.

EXAMPLE 38

The process is carried out as in Example 37 but as starting material2-amino-pyridine-hydrobromide is used instead of 2-amino-pyridinehydrochloride and after a reaction lasting 8 hours 3.3 g. (62%) of2,3-trimethylene-4-oxo-4H-pyrido(1,2-a) pyrimidine hydrobromide areobtained, melting point 275°-277° C. (recrystallized from ethanol).

Analysis for the formula C₁₁ H₁₁ N₂ BrO Calculated: C, 49.46%; H, 4.15%;N, 10.49%; Br, 29.91%; Found: C, 49.80%; H, 4.37%; N, 10.62%; Br,29.85%.

The base is set free from the hydrobromide salt by the usual methods andit is recrystallized from ethanol.2,3-trimethylene-4-oxo-4H-pyrido(1,2-z)pyrimidine is obtained which whenadmixed with the product according to Example 1 does not given anymelting point depression.

EXAMPLE 39

The reaction is carried out according to Example 37, but2-amino-pyridine hydroiodide is used instead of2-amino-pyridine-hydrochloride; the reaction lasts 6 hours and 4.74 g.(76%) of 2,3-trimethylene-4-oxo-4H-pyrido(1,2-a)pyrimidine-hydroiodideare obtained, the product is recrystallized from ethanol and it melts at212° to 214° C.

Analysis for the formula C₁₁ H₁₁ N₂ IO: Calculated: C, 42.06%; H, 3.53%;N, 8.92%; I, 40.40%; Found: C, 41.85%, H, 3.60%; N, 9.09%; I, 40.21%.

EXAMPLE 40

2.31 g. of 2,3-trimethylene-7-nitro-4-oxo-4H-pyrido(1,2-a)pyrimidine and3.9 g. of powdered iron are suspended in 20 ml of water. The reactionmixture is stirred for 3 hours on a water bath, while 3 to 4 ml. ofhydrochloric acid are added dropwise. The mixture is filtered on adraped filter, the filtrate is neutralized with 10% by W/V sodiumhydroxide solution and the precipitated fluffy substance is concentratedby heating. The obtained reaction mixture is shaken out three times withchloroform. The combined chloroform solution is dried over sodiumsulphate, filtrated and evaporated. 0.72 g. (35%) of yellow2,3-trimethylene-7-amino-4-oxo-4H-pyrido(1,2-a)pyrimidine is obtainedand recrystallized from ethanol, melting point: 260°-264° C.

Analysis for the formula C₁₁ H₁₁ N₃ O: Calculated: C, 65.67%; H, 5.51%;N, 20.88%; Found: C, 65.33%; H, 5.40%, N, 20.86%.

EXAMPLE 41

2.0 g. of 2,3-trimethylene-6-methyl-4-oxo-4H-pyrido(1,2-a)pyrimidine aredissolved in 25 ml. of acetone and the solution together with 7.1 g. ofmethyl iodide is filled to a bomb tube. The sealed bomb tube ismaintained at 100° C. for 10 hours. The reaction mixture is cooled andthe bomb tube is opened followed by evaporation to a volume of 15 ml.The reaction mixture is allowed to stand overnight and the precipitatedcrystals are filtered off, and covered with a small amount of acetone.2.15 g. (67%) of yellow1,6-dimethyl-2,3-trimethylene-4-oxo-4H-pyrido(1,2-a)pyrimidinium iodideare obtained, the product is recrystallized from ethanol, m.p. 228°-230°C.

Analysis for the formula C₁₃ H₁₅ N₂ OI: Calculated: C, 45.63%; H, 4.42%;Found: C, 45.62%; H, 4.43%.

EXAMPLE 42

4.0 g. of 2,3-trimethylene-6-methyl-4-oxo-4H-pyrido(1,2-a)pyrimidine aredissolved in 50 ml. of acetone and after adding 2.52 g. ofdimethylsulfate the mixture is boiled for 16 hours. The reaction mixtureis then evaporated to about half volume. The product precipitates oncooling in the form of crystals. The precipitated crystals are filteredand washed with acetone. 4.96 g. (76%) of1,6-dimethyl-2,3-trimethylene-4-oxo-4H-pyrido(1,2-a)pyrimidiniummethyl-sulphate are obtained and crystallized from a mixture of ethanoland ether. M.p.: 148°-150° C.

Analysis for the formula C₁₄ H₁₈ N₂ O₅ S: Calculated: C, 51.52%; H,5.56%; N, 8.58%; Found: C, 51.98%; H, 5.58%; N, 8.53%.

EXAMPLES 43 TO 52

20 mmoles of 4-oxo-4H-pyrido(1,2-a)pyrimidine according to Table 4 aredissolved in 50 ml. of ethanol and the solution is hydrogenated for 3 to6 hours in the presence of 5 g. of Raney nickel catalyst at atmosphericpressure. The theoretical amount of hydrogen is consumed whereafter thehydrogen takeup ceases. The catalyst is removed by filtration, thesolution is evaporated and the residue is crystallized from the givensolvent. The prepared compounds are enumerated in Table 4.

                                      Table 4                                     __________________________________________________________________________                                                          Analysis                                                         Recrystalli- Calculated              Starting                       Yield                                                                              Mp.  zation                                                                              Empirical                                                                            Found                   Example                                                                            material  Product   Catalyst                                                                           %    ° C.                                                                         solvent                                                                             formula                                                                              C                                                                                H                                                                                N                 __________________________________________________________________________                                                                %                 43   2,3-trimethylene-                                                                       2,3-trimethylene-                                                                       Raney                                                     4-oxo-4H-pyrido                                                                         4-oxo-6,7,8,9-                                                                          Ni   96   96-97 petrol-      69.44                                                                            7.42                                                                             14.73                  (1,2-a)pyrimidine                                                                       tetrahydroxo-4H-          ether C.sub.11 H.sub.14 N.sub.2                                                     O                                             pyrido(1,2-a)-                         69.30                                                                            7.59                                                                             14.89                            pyrimidine                                                     44.sup.+                                                                           2,3-tetramethylene-                                                                     2,3-tetramethyl-                                                                        Raney                                                     4-oxo-4H-pyrido-                                                                        ene-4-oxo-6,7,8,9-                                                                      Ni   98   172-173.sup.++                                                                            C.sub.12 H.sub.16 N.sub.2                                                     O      70.56                                                                            7.90                                                                             13.72                  (1,2-a)pyrimidine                                                                       tetrahydro-4H-                         70.45                                                                            8.00                                                                             13.74                            pyrido(1,2-a)-            n-hexane                                            pyrimidine                                                     45   2,3-pentamethyl-                                                                        2,3-pentamethyl-                                                    ene-4-oxo-4H-                                                                           ene-4-oxo-6,7,8,9-                     71.52                                                                            8.31                                                                             12.83                  pyrido(1,2-a)-                                                                          tetrahydro-4H-                                                                          Raney                                                                              95   159         C.sub.13 H.sub.18 N.sub.2                                                     O                                   pyrimidine                                                                              pyrido(1,2-a)-                                                                          Ni              n-hexane     71.49                                                                            8.22                                                                             12.94                            pyrimidine                                                     46   2,3-hexamethyl-                                                                         2,3-hexamethyl-                                                     ene-4-oxo-4H-                                                                           ene-4-oxo-6,7,8,9-                     72.38                                                                            8.68                                                                             12.06                  pyrido(1,2-a)-                                                                          tetrahydro-4H-                                                                          Raney                                                                              97   110         C.sub.14 H.sub.20 N.sub.2                                                     O                                   pyrimidine                                                                              pyrido(1,2-a)-                                                                          Ni              n-hexane     72.22                                                                            8.64                                                                             12.09                            pyrimidine                                                     47   2,3-trimethyl-                                                                          2,3-trimethyl-                                                      ene-4-oxo-4H-                                                                           ene-6-methyl-4-                        70.56                                                                            7.90                                                                             13.72                  pyrido(1,2-a)-                                                                          oxo-6,7,8,9-                                                                            Raney                                                                              96   86-87 petrol-                                                                             C.sub.12 H.sub.16 N.sub.2                                                     O                                   pyrimidine                                                                              tetrahydro-4H-                                                                          Ni              ether        70.44                                                                            7.85                                                                             13.80                            pyrido(1,2-a)-                                                                pyrimidine                                                     48   2-tetramethyl-                                                                          2,3-tetramethyl-                                                                        Raney                                                     ene-6-methyl-4-                                                                         ene-6-methyl-4-                                                                         Ni   97   128-130     C.sub.13 H.sub.18 N.sub.2                                                     O      71.52                                                                            8.31                                                                             12.83                  oxo-4H-pyrido-                                                                          oxo-6,7,8,9-              n-hexane     71.49                                                                            8.22                                                                             12.94                  (1,2-a)pyri-                                                                            tetrahydro-4H-                                                      midine    pyrido(1,2-a)-                                                                pyrimidine                                                     49   2,3-pentamethyl-                                                                        2,3-pentamethyl-                                                                        Raney           petrol-                                   ene-6-methyl-4-                                                                         ene-6-methyl-4-                                                                         Ni   98.5 93-94 ether C.sub.14 H.sub.20 N.sub.2                                                     O      72.38                                                                            8.68                                                                             12.06                  oxo-4H-pyrido-                                                                          oxo-6,7,8,9-                           72.44                                                                            8.81                                                                             12.04                  (1,2-a)-pyrido-                                                                         tetrahydro-4H-                                                      midine    pyrido(1,2-a)-                                                                pyrimidine                                                     50   2,3-hexamethyl-                                                                         2,3-hexamethyl-                                                                         Raney           petrol-                                   ene-6-methyl-4-                                                                         ene-6-methyl-4-                                                                         Ni   94.5 70-71 ether C.sub.15 H.sub.22 N.sub. 2                                                    O      73.13                                                                            9.00                                                                             11.37                  oxo-4H-pyrido-                                                                          oxo-6,7,8,9-                           73.04                                                                            9.10                                                                             11.32                  (1,2-a)pyrimi-                                                                          tetrahydro-4H-                                                      dine      pyrido(1,2-a)-                                                                pyrimidine                                                     51   2,3-(1-methyl-                                                                          2,3-(1-methyl-                                                                          Raney                                                     trimethylene)-                                                                          trimethylene)-6-                                                                        Ni   96   88-91       C.sub.13 H.sub.18 N.sub.2                                                     O      71.52                                                                            8.31                                                                             12.83                  6-methyl-4-oxo-                                                                         methyl-4-oxo-             n-hexane     71.49                                                                            8.22                                                                             12.94                  4H-pyrido(1,2-a)-                                                                       6,7,8,9-tetra-                                                      pyrimidine                                                                              hydro-4H-pyrido-                                                              (1,2-a)pyrimidine                                              52   2,3-(2-tertiary-                                                                        2,3-(2-tertiary-                                                    butyl-trimethyl-                                                                        butyl-trimethyl-                                                                        Raney                        73.80                                                                            9.29                                                                             10.76                  ene)-6-methyl-4-                                                                        ene)-6-methyl-4-                                                                        Ni   95.5 98-100                                                                              ether C.sub.16 H.sub.24 N.sub.2                                                     O                                   oxo-4H-pyrido-                                                                          oxo-6,7,8,9-                           73.76                                                                            9.34                                                                             10.76                  (1,2-a)pyrimidine                                                                       tetrahydro-4H-                                                                pyrido(1,2-a)-                                                                pyrimidine                                                     __________________________________________________________________________     .sup.+ Melting point of hydrochloride salt 185°-195° C.         (ethanolether)                                                                .sup.++ J. Org. Chem. 40, 2201, 1975; Yield 14%; melting point                168°-170° C.                                               

EXAMPLES 53 TO 61

20 mmoles of 4-oxo-4H-pyrido(1,2-a)pyrimidine according to Table 5 aredissolved in 50 ml. of ethanol and the solution is hydrogenated in thepresence of 1 g. 10% by weight palladium on charcoal catalyst atatmospheric pressure. The calculated amount of hydrogen is consumedwithin 6 to 10 hours. The catalyst is filtered off and the reactionmixture is evaporated and crystallized from the given solvent. Theprepared compounds are shown in Table 5.

                                      Table 5                                     __________________________________________________________________________                                                          Analysis                                                         Recrystalli- Calculated              Starting                        Yield                                                                              Mp. zation                                                                              Empirical                                                                            Found                   Example                                                                            material  Product   Catalyst                                                                            %    ° C.                                                                        solvent                                                                             formula                                                                              C                                                                                H                                                                                N                 __________________________________________________________________________                                                                %                 53   2,3-trimethyl-                                                                          2,3-trimethyl-                                                      ene-4-oxo-4H-                                                                           ene-4-oxo-                             69.44                                                                            7.42                                                                             14.73                  pyrido(1,2-a)-                                                                          6,7,8,9-tetra-                                                                          Pd/C  97   97   petrol-                                                                             C.sub.11 H.sub.14 N.sub.2                                                     O      69.40                                                                            7.41                                                                             14.78                  pyrimidine                                                                              hydro-4H-pyrido-          ether                                               (1,2-a)pyri-                                                                  midine                                                         54   2,3-tetramethyl-                                                                        2,3-tetramethyl-                                                    ene-4-oxo-4H-                                                                           ene-4-oxo-6,7,8,9-                     70.56                                                                            7.90                                                                             13.72                  pyrido(1,2-a)-                                                                          tetrahydro-4H-                                                                          Pd/C  98.5 172-173.sup.+                                                                            C.sub.12 H.sub.16 N.sub.2                                                     O      70.63                                                                            7.82                                                                             13.80                  pyrimidine                                                                              pyrido(1,2-a)-            n-hexane                                            pyrimidine                                                     55   2,3-pentamethyl-                                                                        2,3-pentamethyl-                                                    ene-4-oxo-4H-                                                                           ene-4-oxo-6,7,8,9-                     71.52                                                                            8.31                                                                             12.83                  pyrido(1,2-a)-                                                                          tetrahydro-4H-                                                                          Pd/C  94.5 158-159    C.sub.13 H.sub.18 N.sub.2                                                     O      71.42                                                                            8.25                                                                             13.01                  pyrimidine                                                                              pyrido(1,2-a)-            n-hexane                                            pyrimidine                                                     56   2,3-hexamethyl-                                                                         2,3-hexamethyl-                                                     ene-4-oxo-4H-                                                                           ene-4-oxo-6,7,8,9-                     72.38                                                                            8.68                                                                             12.06                  pyrido(1,2-a)-                                                                          tetrahydro-4H-                                                                          Pd/C  96   110  n-hexane                                                                            C.sub.14 H.sub.20 N.sub.2                                                     O      72.31                                                                            8.72                                                                             12.10                  pyrimidine                                                                              pyrido(1,2-a)-                                                                pyrimidine                                                     57   2,3-trimethyl-                                                                          2,3-trimethyl-                                                      ene-6-methyl-4-                                                                         ene-6-methyl-4-           petrol-      70.56                                                                            7.90                                                                             13.72                  oxo-4H-pyrido-                                                                          oxo-6,7,8,9-                                                                            Pd/C  94   86-87                                                                              ether C.sub.12 H.sub.16 N.sub.2                                                     O      70.51                                                                            7.98                                                                             13.69                  (1,2-a)pyrimidine                                                                       tetrahydro-4H-                                                                pyrido(1,2-a)-                                                                pyrimidine                                                     58   2,3-tetramethyl-                                                                        2,3-tetramethyl-                                                    ene-6-methyl-4-                                                                         ene-6-methyl-4-                                                     oxo-4H-pyrido-                                                                          oxo-6,7,8,9-tetra-                                                                      Pd/C  98   129-130                                                                            n-hexane                                                                            C.sub.13 H.sub.18 N.sub.2                                                     O      71.52                                                                            8.31                                                                             12.83                  (1,2-a)-pyrimidine                                                                      hydro-4H-pyrido-                       71.60                                                                            8.28                                                                             12.85                            (1,2-a)-pyri-                                                                 midine                                                         59   2,3-pentamethyl-                                                                        2,3-pentamethyl-                                                    ene-6-methyl-4-                                                                         ene-6-methyl-4-                                                     oxo-4H-pyrido-                                                                          oxo-6,7,8,9-tetra-        petrol-      72.38                                                                            8.68                                                                             12.06                  (1,2-a)-pyrimidine                                                                      hydro-4H-pyrido-                                                                        Pd/C  96   94   ether C.sub.14 H.sub.20 N.sub.2                                                     O      72.25                                                                            8.72                                                                             12.10                            (1,2-a)-pyri-                                                                 midine                                                         60   2,3-hexamethyl-                                                                         2,3-hexamethyl-                                                     ene-6-methyl-4-                                                                         ene-6-methyl-4-                                                     oxo-4H-pyrido-                                                                          oxo-6,7,8,9-tetra-        petrol-      73.13                                                                            9.00                                                                             11.37                  (1,2-a)-pyrimidine                                                                      hydro-4H-pyrido-                                                                        Pd/C  97.5 70-71                                                                              ether C.sub.15 H.sub.22 N.sub.2                                                     O      73.21                                                                            8.95                                                                             11.44                            (1,2-a)-pyri-                                                                 midine                                                         61   2,3-(1-methyl-                                                                          2,3-(1-methyl-                                                      trimethylene)-6-                                                                        trimethylene)-6-                                                    methyl-4-oxo-4H-                                                                        methyl-4-oxo-                          71.52                                                                            8.31                                                                             12.83                  pyrido(1,2-a)-                                                                          6,7,8,9-tetra-                                                                          Pd/C  96.5 89-91                                                                              n-hexane                                                                            C.sub.13 H.sub.18 N.sub.2                                                     O      71.48                                                                            8.42                                                                             12.75                  pyrimidine                                                                              hydro-4H-pyrido-                                                              (1,2-a)-pyri-                                                                 midine                                                         62   2,3-(2-tertiary-                                                                        2,3-(2-tertiary-                                                    butyl-trimethyl-                                                                        butyl-trimethyl-                       73.80                                                                            9.29                                                                             10.76                  ene)-6-methyl-4-                                                                        ene)-6-methyl-4-                                                                        Pd/C  98   99-100                                                                             ether C.sub.16 H.sub.24 N.sub.2                                                     O                                   oxo-4H-pyrido-                                                                          oxo-6,7,8,9-tetra-                     73.84                                                                            9.30                                                                             10.87                  (1,2-a)-pyrimidine                                                                      hydro-4H-pyrido-                                                              (1,2-a)-pyrimidine                                             __________________________________________________________________________     +J. Org. Chem. 40, 2201, 1975; yield 14%; melting point 168° to        170° C.                                                           

EXAMPLE 63

2.7 g. of 2-amino-3,4,5,6-tetrahydro-pyridine hydrochloride are treatedin 20 ml. of ethanol with an equivalent amount of sodium ethylate. Theprecipitated sodium chloride is removed by filtration and 3.4 g. of2-ethoxycarbonyl-1-oxo-cyclohexane are added to the obtained solution,followed by the boiling of the reaction mixture for 1 hour. The reactionmixture is evaporated. The residue is crystallized from a mixture ofacetone and hexane. 3.02 g. (74%) of2,3-tetramethylene-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidineare obtained, melting point: 171°-172° C. and no melting pointdepression is shown by admixing the product with the product of Example44 or 54.

EXAMPLE 64 to 67

55 mmoles of 2-amino-1-cyclohexane-carboxylic acid according to Table 6and 5 mmoles of lactimether are boiled for 5 hours in 20 ml. ofchlorobenzene and the reaction mixture is evaporated to dryness and theresidue is dissolved with 4×25 ml. of ether. The ether solution isevaporated. The obtained product is recrystallized from the givensolvent according to Table 6. The prepared products and data thereof areshown in Table 6.

                                      Table 6                                     __________________________________________________________________________    Starting material                                                             2-amino-1-                                            Analysis                cyclohexane-                             Recrystalli- Calculated              carboxylic   lacti-           Yield                                                                              Mp.   zation                                                                              Empirical                                                                            Found                   Example                                                                            acid    mether                                                                              Product    %    ° C.                                                                         solvent                                                                             formula                                                                              C                                                                                H                                                                                N                 __________________________________________________________________________                                                                %                 64   cis-2-amino-                                                                          2-ethoxy-                                                                           2,3-cis-2,3-(tetra-                                             1-cyclohexane-                                                                        3,4,5,6-                                                                            methylene)-4-oxo-                  69.87                                                                            8.80                                                                             13.58                  carboxylic                                                                            tetrahydro-                                                                         6,7,2,3,8,9-hexa-                                                                        88   68-71 ether C.sub.12 H.sub.18 N.sub.2                                                     O      69.44                                                                            8.66                                                                             13.46                  acid    pyridine                                                                            hydro-4H-pyrido-                                                              (1,2-a)pyrimidine                                          65   trans-2-ami-                                                                          2-ethoxy-                                                                           2,3-trans-(tetra-                                               no-1-cyclo-                                                                           3,4,5,6-                                                                            methylene)-4-oxo-                  69.87                                                                            8.80                                                                             13.58                  hexane-car-                                                                           tetrahydro-                                                                         2,3,6,7,8,9-hexa-                                                                        79   129-130                                                                             petrol-                                                                             C.sub.12 H.sub.18 N.sub.2                                                     O      69.71                                                                            8.81                                                                             13.62                  boxylic acid                                                                          pyridine                                                                            hydro-4H-pyrido-      ether                                                   (1,2-a)pyrimidine                                          66   cis-2-amino-                                                                          2-ethoxy-                                                                           2,3-cis-(tetra-                                                 1-cyclohexane-                                                                        4,5,6,7-                                                                            methylene)-4-oxo-                  70.87                                                                            9.15                                                                             12.72                  carboxylic                                                                            tetrahydro-                                                                         2,3,4,6,7,8,9,10-                                                                        55    81-82.sup.+                                                                        ether C.sub.13 H.sub.20 N.sub.2                                                     O      71.36                                                                            8.92                                                                             12.61                  acid    3H-azepine                                                                          octahydro-azepino-                                                            (1,2-a)pyrimidine                                          67   cis-2-amino-                                                                          2-ethoxy                                                                            2,3-cis-(tetra-                                                 1-cyclohexane                                                                         5-tertiary-                                                                         methylene)-8-tertiary                                           carboxylic                                                                            butyl-4,5,-                                                                         butyl-4-oxo-2,3,4,6,-              73.86                                                                            10.21                                                                            10.13                  acid    6,7-tetra-                                                                          7,8,9,10-octahydro-                                                                      74   96-100                                                                              n-hexane                                                                            C.sub.17 H.sub.28 N.sub.2                                                     O      73.57                                                                            10.17                                                                            10.25                          hydro-3H-                                                                           azepino-(1,2-a)-                                                        azepine                                                                             pyrimidine                                                 __________________________________________________________________________     .sup.+ GFR Pat. No. 1 088 968. Melting point 100° C.              

EXAMPLES 68 to 71

5 mmoles of tricyclic nitrogen bridge-head compounds are dissolved in 5ml. of methanol and 10 mmoles of sodiumborohydride dissolved in 10 ml.of water are added dropwise to the methanolic solution under shaking.After 2 hours reaction time the excess of the reducing agent isdecomposed with a few drops of acetic acid and the excess of acetic acidis neutralized with sodiumbicarbonate solution. The methanol isdistilled off and the aqueous part is extracted with 3×20 ml. of etherand evaporated after drying. The white crystalline residue iscrystallized from ether. The prepared products and data thereof areshown in Table 7.

                                      Table 7                                     __________________________________________________________________________    Starting material                                     Analysis                tricyclic compound                       Recrystalli- Calculated              having nitrogen               Yield                                                                              Mp.   zation                                                                              Empirical                                                                            Found                   Example                                                                            bridge-head  Product     %    ° C.                                                                         solvents                                                                            formula                                                                              C                                                                                H                                                                                N                 __________________________________________________________________________                                                                %                 68   2,3-cis-(tetramethyl-                                                                      2,3-cis-(tetramethyl-                                            ene)-4-oxo-2,3,6,7,8,9-                                                                    ene)-4-oxo-1,2,3,6,7,                                                                     76   111-113                                                                             ether C.sub.12 H.sub.20 N.sub.2                                                     O      69.19                                                                            9.68                                                                             13.45                  hexahydro-4H-pyrido-                                                                       8,9,9a-octahydro-4H-                69.22                                                                            9.74                                                                             14.51                  (1,2-a)pyrimidine                                                                          pyrido(1,2-a)pyri-                                                            midine      midine                                          69   2,3-trans-(tetra-                                                                          2,3-trans-(tetra-                                                methylene)-4-oxo-2,3,6,-                                                                   methylene)-4-oxo-                                                7,8,9-hexahydro-4H-                                                                        1,2,3,6,7,8,9,9a-                                                                         77   175-176                                                                             ether C.sub.12 H.sub.20 N.sub.2                                                     O      69.19                                                                            9.68                                                                             13.45                  pyrido(1,2-a)pyri-                                                                         octahydro-4H-pyrido-                69.07                                                                            9.46                                                                             13.39                  midine       (1,2-a)pyrimidine                                           70   2,3-cis-(tetra-                                                                            2,3-cis-(tetra-                                                  methylene-4-oxo-2,3,4,                                                                     methylene)-4-oxo-                   70.23                                                                            9.97                                                                             12.60                  6,7,8,9,10-octahydro-                                                                      1,2,3,4,6,7,8,9,10,                                                                       72   126-128                                                                             ether C.sub.13 H.sub.22 N.sub.2                                                     O      70.16                                                                            9.89                                                                             12.62                  azepino (1,2-a) pyrimidine                                                                 10a-decahydro-azepino-                                                        (1,2-a) pyrimidine                                          71.sup.+                                                                           2,3-cis-(tetra-                                                                            2,3-cis-(tetra-                                                  methylene)-8-tertiary-                                                                     methylene)-8-                       73.33                                                                            10.86                                                                            10.06                  butyl-4-oxo-2,3,4,6,7,                                                                     tertiary-butyl-4-                                                                         70   154-156                                                                             ether C.sub.17 H.sub. 30 N.sub.2                                                    O      73.20                                                                            10.72                                                                            9.98                   8,9,10-octahydro-                                                                          oxo-1,2,3,4,6,7,8,9,                                             azepino (1,2-a)                                                                            10,10a-decahydro-                                                pyrimidine   azepino-(1,2-a)pyrimidine                                   __________________________________________________________________________     .sup.+ Hydrochloride salt melts at 258°-261° C.                 (ethanolether)-                                                          

EXAMPLE 72

20 mmoles of2,3-trimethylene-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidineare dissolved in 50 ml. of acetone and 20 mmoles of dimethylsulphate areadded to the reaction mixture which is boiled for 8 hours. The acetoneis evaporated to half volume and after cooling the precipitated crystalsare filtered and covered with a small amount of acetone. 73.5% of white1,6-dimethyl-2,3-trimethylene-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidiniummethylsulphate is obtained, which after recrystallization from a mixtureof acetone and ether melts at 129° to 132° C.

Analysis for the formula C₁₄ H₂₂ N₂ O₅ S: Calculated: C, 50.90%; H,6.71%; N, 8.47%; Found: C, 50.52%; H, 6.77%; N, 8.32%.

EXAMPLE 73

The reaction is set forth as in Example 72 but2,3-tetramethylene-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidineis substituted for2,3-trimethylene-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidineand thus snowwhite1,6-dimethyl-2,3-tetramethylene-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidiniummethyl sulphate is obtained with a yield of 71%, which is crystallizedfrom acetone and melts at 155°-157° C.

Analysis for C₁₅ H₂₄ N₂ O₅ S: Calculated: C, 52.31%; H, 7.02%; N, 8.12%;Found: C, 52.53%; H, 7.08%; N, 8.06%.

EXAMPLE 74

3.3 g. of1,6-dimethyl-2,3-trimethylene-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidiniummethyl sulphate are dissolved in 15 ml. of water and a solution of 10mmoles of sodiumborohydride in 10 ml. of water is added under shaking.The reaction mixture is heated to 34° to 45° C. After 2 hours' reactiontime the excess of the reducing agent is decomposed with acetic acid andthe excess of the acid is neutralized with sodium bicarbonate. Thereaction mixture is shaken out with 3×25 ml. of chloroform. Thechloroform solution is evaporated after drying. The residue is distilledin vacuo from a Hickmann flask. The main cut is distilled at 128°-129°C. at 4 Hg mm. 1.8 g. (81%) of1,6-dimethyl-2,3-trimethylene-4-oxo-1,2,3,6,7,8,9,9a-octahydro-4H-pyrido(1,2-a)pyrimidineis obtained in the form of a non-crystallizable oil. The hydrochloridesalt obtained from the product melts at 223°-227° C. afterrecrystallization from ethanol-ether mixture.

Analysis for the formula C₁₃ H₂₂ N₂ O-HCl: Calculated: C, 60.34%; H,8.96%; Cl_(ionic), 13.70%; Found: C, 60.41%; H,9.12%; Cl_(ionic),13.28%.

EXAMPLE 75

15.6 g. of 2-ethoxycarbonyl-1-oxo-cyclopentane and 11.1 g. of2-amino-3-hydroxy-pyridine are reacted according to Example 36 and thus10.2 g. of crystalline2.3-trimethylene-9-hydroxy-4-oxo-4H-pyrido(1,2-a)pyrimidine areobtained, m.p. 152°-156° C. and after recrystallization from 70% ethanolthe product did not show any melting point depression with the compoundprepared according to Example 8.

EXAMPLE 76

2-Amino-4-methyl-pyridine-hydrochloride was reacted with2-ethoxy-carbonyl-1-oxo-cyclopentane according to Example 37 and thus2.08 g. (44%) of2,3-trimethylene-8-methyl-4-oxo-4H-pyrido(1,2-a)pyrimidine-hydrochloridewas obtained, melting point: 200°-205° C. and thus no melting pointdepression is given with a compound obtained according to Example 24.

EXAMPLE 77

0.02 moles of 2-ethoxycarbonyl-1-imino-cyclopentane and 0.02 moles of2-methoxy-3,4,5,6-tetrahydro-pyridine are stirred in 20 g. ofpolyphosphoric acid for 30 minutes at 70° C. and for 30 minutes at 120°C. The reaction mixture is diluted with 20 ml. of water and the pH-valueof the solution is adjusted with 10% by W/V sodium hydroxide solution toneutral. The solution is extracted with 3×25 ml. of chloroform and thecombined extract is evaporated after drying. The yellow residue ischromatographed with 30 g. of alumina of activity II (solvent:petrolether) and the obtained fractions are analyzed by thin layerchromatography, (silicagel plate, benzene:ethanol:4:1) and thecorresponding fractions are evaporated and thus 0.38 g. (10%) of2,3-trimethylene-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine areobtained, melting point: 95°-96° C., and the product does not give anymelting point depression with the product of the Example 43 or 53.

EXAMPLE 78

0.02 moles of 2-iminopyrrolidine-hydrochloride is reacted with anequivalent amount of sodium ethylate and2-ethoxycarbonyl-1-oxo-cyclohexane according to Example 63.2,3-trimethylene-6,7,8,9-tetrahydro-4-oxo-quinazoline is obtained.Yield: 63%. The mixture is crystallized from a mixture of acetone andhexane. Melting point: 120°-121° C.

Analysis for the formula C₁₁ H₁₄ N₂ O: Calculated: C, 69.44%; H, 7.42%;N, 14.73%; Found: C, 69.23%; H, 7.40%; N, 14.91%.

EXAMPLE 79

0.02 moles of 2-ethoxycarbonyl-1-oxo-cyclohexane is reacted with 0.02moles of 2-amino-nicotinic acid according to Examples 1 to 20.2,3-tetramethylene-9-carboxy-4-oxo-4H-pyrido(1,2-a)pyrimidine is formed.Yield: 46%. The product is recrystallized from ethanol, melting point:202°-204° C.

Analysis for the formula C₁₃ H₁₂ N₂ O₃ : Calculated: C, 63.92%; H,4.95%; Found: C, 63.96%; H, 4.95%.

EXAMPLE 80

0.02 moles of 2-ethoxycarbonyl-1-oxo-cyclohexane is reacted with 0.02moles of 2-amino-3-ethoxycarbonyl-pyridine according to Example 1 to 20.2,3-tetramethylene-9-ethoxycarbonyl-4-oxo-4H-pyrido(1,2-a)pyrimidine isobtained. Yield: 63%. After recrystallization from ethanol the productmelts at 143°-144° C.

Analysis for the formula C₁₅ H₁₆ N₂ O₃ : Calculated: C, 66.16%; H,5.92%; Found: C, 66.20%; H, 5.87%.

EXAMPLE 81

1 g. of 2,3-tetramethylene-9-carboxy-4-oxo-4H-pyrido(1,2-a)pyrimidine(of Example 79) is refluxed for 3 hours in 20 ml. of 20% W/V by ofethanol containing hydrochloric acid. The solution is evaporated todryness and thus yellow crystals are obtained, which are dissolved in 25ml. of water and neutralized with saturated sodiumbicarbonate solution.The precipitated 0.92 g. of (82%) of2,3-tetramethylene-9-ethoxycarbonyl-4-oxo-4H-pyrido(1,2-a)pyrimidine isrecrystallized from ethanol, melting point: 144°-145° C. The productdoes not give any melting point depression with the product of Example80.

EXAMPLE 82

0.02 moles of 2-ethoxycarbonyl-1-oxo-cyclohexane is reacted with 0.02moles of 6-aminonicotinic acid according to Example 1 to 20.2,3-tetramethylene-7-carbamoyl-4-oxo-4H-pyrido(1,2-a)pyrimidine isobtained. Yield: 41%. Melting point after recrystallization 313°-315° C.

Analysis for the formula C₁₃ H₁₃ N₃ O₂ : Calculated: C, 64.18%; H,5.39%; N, 17.28%; Found: C, 64.22%; H, 5.61%.

EXAMPLE 83

0.02 moles of 2-ethoxycarbonyl-1-oxo-cyclohexane is reacted with 0.02moles of 2-amino-5-ethoxycarbonyl-pyridine according to Examples 1 to20. 2,3-tetramethylene-7-ethoxycarbonyl-4-oxo-4H-pyrido(1,2-a)pyrimidineis obtained. Yield: 67%. Melting point after recrystallization fromether: 100°-102° C.

Analysis for the formula C₁₅ H₁₆ N₂ O₃ : Calculated: C, 66.16%; H,5.92%; Found: C, 66.20%; H, 6.02%.

EXAMPLE 84

0.02 moles of 2-ethoxycarbonyl-1-oxo-cyclohexane is reacted with 0.02moles of 6-amino-nicotinic acid according to Example 36.2,3-tetramethylene-7-carboxy-4-oxo-4H-pyrido(1,2-a)pyrimidine isobtained. Yield: 44%. After recrystallization from ethanol the productmelts at 256°-258° C.

Analysis for the formula C₁₃ H₁₂ N₂ O₃ : Calculated: C, 63.92%; H,4.95%; Found: C, 63.84%; H, 5.00%.

EXAMPLE 85

0.02 moles of 2-ethoxycarbonyl-1-oxo-cyclohexane and 0.02 moles of6-amino-nicotinic acid are stirred for 2 hours at 110° C. in the mixtureof 10 ml. of phosphorus trichloride oxide and 2 g. of polyphosphoricacid. The reaction mixture is decomposed with 20 ml. of ethanol at 70°to 80° C. and the solution is neutralized under cooling with ice with a10% by W/V solution hydroxide solution. The ethanol is evaporated andthe residue is extracted with 4×25 ml. of chloroform. The combinedextract is evaporated after drying and the residue is crystallized aftertrituration with ether.2,3-tetramethylene-7-ethoxycarbonyl-4-oxo-4H-pyrido(1,2-a)pyrimidine isobtained, yield: 40%. The product is recrystallized from ether, meltingpoint: 101°-102° C., the product does not give melting point depressionwith the product according to Example 83.

EXAMPLE 86

0.02 moles of 2-ethoxycarbonyl-1-oxo-cyclohexane is reacted with 0.02moles of 2-amino-5-ethoxycarbonylpyridine according to Example 85.2,3-Tetramethylene-7-ethoxycarbonyl-4-oxo-4H-pyrido(1,2-a)pyrimidine isobtained. Yield: 49%. The product is recrystallized from ether, meltingpoint: 100°-102° C. The product does not give melting point depressionwith a product of Example 83 or 85.

EXAMPLE 87

2,3-tetramethylene-7-carboxy-4-oxo-4H-pyrido(1,2-a)pyrimidine preparedaccording to Example 84 is esterified with ethanol as in Example 81.2,3-Tetramethylene-7-ethoxycarbonyl-4-oxo-4H-pyrido(1,2-a)pyrimidine isobtained. Yield: 91%. After recrystallization from ether the meltingpoint is at 101°-102° C., no melting point depression is given whenadmixed with the products according to Examples 83, 85 and 86.

EXAMPLE 88

2.82 (0.02 moles) of 2-oxocyclohexane-1-carboxamide and 1.88 g. (0.02moles) of 2-amino-pyridine are heated in 20 g. of polyphosphoric acid onwaterbath under stirring for 1.5 hours. The reaction mixture is pouredto 20 ml. of water and neutralized with 10% by W/V sodium hydroxidesolution. The precipitated crystals are filtered and washed with water.2.6 g. (46%) of 2,3-tetramethylene-4-oxo-4H-pyrido(1,2-a)pyrimidine areobtained. After recrystallization from diisopropylether the productmelts at 103° C. and no melting point depression is given when admixedwith the product prepared according to Example 12.

What we claim is:
 1. A compound of the formula: ##STR8## wherein R is a6- or a 7-position halogen, C₁ to C₄ alkyl, nitro, amino, carboxy,methoxycarbonyl, ethoxycarbonyl or carbamoyl;R¹ is a 6- or a 7-positionhydrogen or C₁ to C₄ alkyl or is 8-methyl; R² is hydrogen or C₁ to C₄alkyl; R³ is hydrogen; R⁴ is hydrogen or C₁ to C₄ alkyl or R³ and R⁴form a chemical bond; R⁵ is hydrogen; R⁶ is hydrogen or R⁵ and R⁶ form achemical bond; and m is 1 or 2;or a pharmaceutically acceptable acidaddition or quaternary salt thereof.
 2. The compound defined in claim 1selected from the group which consistsof:2,3-trimethylene-6-methyl-4-oxo-4H-pyrido(1,2-a)pyrimidine;2,3-trimethylene-7-methyl-4-oxo-4H-pyrido(1,2-a)pyrimidine;2,3-trimethylene-6,8-dimethyl-4-oxo-4H-pyrido(1,2-a)pyrimidine;2,3-trimethylene-7-chloro-4-oxo-4H-pyrido(1,2-a)pyrimidine;2,3-trimethylene-7-nitro-4-oxo-4H-pyrido(1,2-a)pyrimidine;2,3-(1-methyl-trimethylene)-6-methyl-4-oxo-4H-pyrido(1,2-a)pyrimidine:2,3-(2-t-butyl-trimethylene)-6-methyl-4-oxo-4H-pyrido(1,2-a)pyrimidine;2,3-tetramethylene-6-methyl-4-oxo-4H-pyrido(1,2-a)pyrimidine;2,3-trimethylene-7-amino-4-oxo-4H-pyrido(1,2-a)pyrimidine;2,3-trimethylene-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)-pyrimidine;2,3-tetramethylene-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)-pyrimidine;2,3-(1-methyl-trimethylene)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine;2,3(2-t-butyl-trimethylene)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine;2,3-tetramethylene-7-ethoxycarbonyl-4-oxo-4H-pyrido(1,2-a)pyrimidine;and 2,3-tetramethylene-7-carboxy-4-oxo-4H-pyrido(1,2-a)pyrimidine; or apharmaceutically acceptable acid addition or quaternary salt thereof. 3.A compound of the formula: ##STR9## wherein R is hydrogen, hydroxy or C₁to C₄ alkyl;R¹ is hydrogen or C₁ to C₄ alkyl; R² is hydrogen or C₁ to C₄alkyl; R³ is hydrogen; R⁴ is hydrogen or C₁ to C₄ alkyl or R³ and R⁴form a chemical bond; R⁵ is hydrogen; R⁶ is hydrogen or R⁵ and R⁶ form achemical bond; and m is 3 or 4;or a pharmaceutically acceptable acidaddition or quaternary salt thereof.
 4. A compound of the formula:##STR10## wherein R is hydrogen or C₁ to C₄ alkyl;R¹ is hydrogen or C₁to C₄ alkyl; R² is hydrogen or C₁ to C₄ alkyl; R³ is hydrogen; R⁴ ishydrogen or C₁ to C₄ alkyl or R³ and R⁴ form a chemical bond; R⁵ ishydrogen; R⁶ is hydrogen or R⁵ and R⁶ form a chemical bond; and n is 2;or a pharmaceutically acceptable acid addition or quaternary saltthereof.
 5. The compound defined in claim 3 selected from the groupconsisting of:2,3-pentamethylene-4-oxo-4H-pyrido(1,2-a)pyrimidine;2,3-pentamethylene-6-methyl-4-oxo-4H-pyrido(1,2-a)pyrimidine;2,3-pentamethylene-9-hydroxy-4-oxo-4H-pyrido(1,2-a)pyrimidine;2,3-hexamethylene-6-methyl-4-oxo-4H-pyrido(1,2-a)pyrimidine;2,3-hexamethylene-4-oxo-4H-pyrido(1,2-a)pyrimidine;2,3-hexamethylene-9-hydroxy-4-oxo-4H-pyrido(1,2-a)pyrimidine;2,3-pentamethylene-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine;2,3-hexamethylene-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine;2,3-pentamethylene-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-(1,2-a)pyrimidine;and2,3-hexamethylene-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-(1,2-a)pyrimidine;or a pharmaceutically acceptable acid addition or quaternary saltthereof.
 6. The compound defined in claim 4 selected from the groupconsistingof:2,3-cis-(tetramethylene)-4-oxo-2,3,4,6,7,8,9,10-octahydro-azepino-(1,2-a)pyrimidine;2,3-cis-(tetramethylene)-8-t-butyl-4-oxo-2,3,4,6,7,8,9,10-octahydro-azepino(1,2-a)pyrimidine;2,3-cis-(tetramethylene)-4-oxo-1,2,3,4,6,7,8,9,10,10a-decahydro-azepino(1,2-a)pyrimidine;and2,3-cis-(tetramethylene)-8-t-butyl-4-oxo-1,2,3,4,6,7,8,9,10,10-decahydro-azepino(1,2-a)pyrimidine;or a pharmaceutically acceptable acid addition or quaternary saltthereof.
 7. A compound selected from the group consistingof:7-methyl-2,3-trimethylene-4-oxo-4H-pyrido(1,2-a)pyrimidine;6,8-dimethyl-2,3-trimethylene-4-oxo-4H-pyrido(1,2-a)pyrimidine;6-methyl-2,3-tetramethylene-4-oxo-4H-pyrido(1,2-a)pyrimidine;2,3-pentamethylene-4-oxo-4H-pyrido(1,2-a)pyrimidine; and2,3-hexamethylene-4-oxo-4H-pyrido(1,2-a)pyrimidine; or apharmaceutically acceptable acid addition or quaternary salt thereof. 8.6,8-Diemthyl-2,3-trimethylene-4-oxo-4H-pyrido(1,2-a)pyrimidine or apharmaceutically effective acid-addition or quaternary salt thereof asdefined in claim
 1. 9.6-Methyl-2,3-tetramethylene-4-oxo-4H-pyrido(1,2-a)pyrimidine or apharmaceutically effective acid-addition or quaternary salt thereof asdefined in claim 1.